Live attenuated SIV deletion mutants remain the gold standard for vaccine protection against SIV239, SIV251 and other similar AIDS-inducing strains in rhesus monkeys. Viral persistence and persistence of immune responses that are up, on, and active at the time of challenge may be one important factor for why the live attenuated vaccine approach protects so well against SIV challenge. The goal of the proposed studies is to determine whether durable cellular and humoral immune responses induced by a persisting herpesvirus can match, or come close to matching, the live attenuated approach for the potency and durability of protection. A gamma-2 herpesvirus (rhesus monkey rhadinovirus; RRV) will be used to express SIV antigens and to analyze protective capabilities in rhesus monkeys. The biological properties and gene content of the gamma herpesviruses differ from those of the alpha and beta herpesviruses and this in turn may influence the qualitative nature of the immune response and ability to provide protection against SIV/HIV. The persistence of RRV vaccine vectors may also be conveniently monitored in the blood and lymphoid organs. Promoter usage, nature of the expression cassette, site of insertion into the RRV genome, and route of administration will be varied in order to optimize the induction of protective immunity. Our studies address the fundamental utility of recombinant, persisting RRV as a vaccine vehicle. They are not directly directed toward trials in people in the near future. Nonetheless, it is relevant to note that a live attenuated herpesvirus vaccine is currently used in humans for varicella zoster and that human infection by the RRV-related virus of humans (KSHV; HHV-8) is rather infrequent (<3%) in North American and European populations. Thus, it is not unreasonable to envision a recombinant KSHV that is missing several genes and capable of expressing HIV antigens for use as a vaccine in people.